US2023321094A1PendingUtilityA1

Combination therapies with olig2 inhibitors

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Assignee: CURTANA PHARMACEUTICALS INCPriority: Aug 24, 2020Filed: Aug 23, 2021Published: Oct 12, 2023
Est. expiryAug 24, 2040(~14.1 yrs left)· nominal 20-yr term from priority
Inventors:Graham BeatonGregory SteinGordon Robert Alton
A61K 31/519A61K 31/502A61K 31/5377A61K 31/505A61K 45/06A61P 35/00A61P 25/00A61K 31/4706A61K 31/506A61K 31/517A61K 31/436A61K 31/4965A61P 43/00A61K 2300/00
53
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Claims

Abstract

Described herein are pharmaceutical compositions containing compounds which inhibit the activity of Olig2 in combination with a second therapeutic agent. Also described herein are methods of using such pharmaceutical compositions for treating cancer and other diseases.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A pharmaceutical composition comprising 1) a first therapeutic agent, 2) a second therapeutic agent, and 3) at least one pharmaceutically acceptable excipient, wherein the first therapeutic agent is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having the structure: 
       
         
           
           
               
               
           
         
         wherein:
 each R 1  is independently halogen, —CN, —NO 2 , —OH, —OCF 3 , —OCH 2 F, —OCF 2 H, —SR 8 , —N(R 8 )S(═O) 2 R 9 , —S(═O) 2 N(R 8 ) 2 , —S(═O)R 9 , —S(═O) 2 R 9 , —C(═O)R 9 , —CO 2 R 8 , —N(R 8 ) 2 , —C(═O)N(R 8 ) 2 , —N(R 8 )C(═O)R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted C 2 -C 7 heteroaryl; 
 or two R 1  are taken together to form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted carbocyclic ring; 
 R 2  and R 3  are each independently H, —CN, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or C 2 -C 7 heterocycloalkyl; or R 2  and R 3  are taken together to form a 5- or 6-membered heterocyclic ring; 
 R 4  is H, halogen, —CN, —NO 2 , —OH, —OCF 3 , —OCH 2 F, —OCF 2 H, —SR 8 , —N(R 8 )S(═O) 2 R 9 , —S(═O) 2 N(R 8 ) 2 , —S(═O)R 9 , —S(═O) 2 R 9 , —C(═O)R 9 , —CO 2 R 8 , —N(R 8 ) 2 , —C(═O)N(R 8 ) 2 , —N(R 8 )C(═O)R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted C 2 -C 7 heteroaryl; 
 R 5  is halogen, —CN, —OH, —CF 3 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted C 2 -C 7 heteroaryl; 
 R 6  is —(C(R 14 )(R 15 )) m N(R 11 )(R 12 ); 
 R 11  and R 12  are each independently H, or substituted or unsubstituted C 1 -C 6 alkyl; or R 11  and R 12  are taken together to form a substituted or unsubstituted 5-, 6-, 7-, or 8-membered heterocyclic ring; 
 each R 14  and R 15  are each independently H, or substituted or unsubstituted C 1 -C 6 alkyl; or 
 R 14  and R 15  are taken together to form a 4-, 5-, 6-membered cycloalkyl ring; 
 each R 8  is independently H, or substituted or unsubstituted C 1 -C 6 alkyl; 
 each R 9  is independently substituted or unsubstituted C 1 -C 6 alkyl; 
 R 10  is H, or C 1 -C 4 alkyl; 
 m is 2-6; and 
 n is 0-4. 
 
       
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein R 2  and R 3  are each independently H, —CN, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or C 2 -C 7 heterocycloalkyl. 
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein R 2  and R 3  are each H. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein R 2  and R 3  are taken together to form a 5- or 6-membered heterocyclic ring. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein R 2  and R 3  are taken together to form a 5-membered heterocyclic ring. 
     
     
         6 . The pharmaceutical composition of any one of  claims 1 - 5 , wherein R 6  is —(C(R 14 )(R 15 )) m N(R 11 )(R 12 ) and R 14  and R 15  are each H. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein R 11  and R 12  are each independently H, or substituted or unsubstituted C 1 -C 6 alkyl. 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein R 11  and R 12  are each independently unsubstituted C 1 -C 6 alkyl. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein R 11  and R 12  are each —CH 3 . 
     
     
         10 . The pharmaceutical composition of any one of  claims 1 - 9 , wherein m is 2. 
     
     
         11 . The pharmaceutical composition of any one of  claims 1 - 9 , wherein m is 3. 
     
     
         12 . The pharmaceutical composition of any one of  claims 1 - 11 , wherein R 10  is H or CH 3 . 
     
     
         13 . The pharmaceutical composition of any one of  claims 1 - 12 , wherein R 8  is substituted or unsubstituted C 1 -C 6 alkyl. 
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein R 5  is CH 3 . 
     
     
         15 . The pharmaceutical composition of  claim 13 , wherein R 8  is CH 2 CH 3 . 
     
     
         16 . The pharmaceutical composition of any one of  claims 1 - 15 , wherein R 4  is H, halogen, —CN, —NO 2 , —OH, —OCF 3 , —OCH 2 F, —OCF 2 H, —SR 8 , —N(R 8 )S(═O) 2 R 9 , —S(═O) 2 N(R 8 ) 2 , —S(═O)R 9 , —S(═O) 2 R 9 , —C(═O)R 9 , —CO 2 RR, —N(R 8 ) 2 , —C(═O)N(R 8 ) 2 , —N(R 8 )C(═O)R 9 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 alkoxy. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein R 4  is H, halogen, —CN, —OH, —OCF 3 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 alkoxy. 
     
     
         18 . The pharmaceutical composition of  claim 16 , wherein R 4  is H, halogen, —OCF 3 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy. 
     
     
         19 . The pharmaceutical composition of  claim 16 , wherein R 4  is halogen. 
     
     
         20 . The pharmaceutical composition of any one of  claims 1 - 19 , wherein each R 1  is independently halogen, —CN, —NO 2 , —OH, —OCF 3 , —OCH 2 F, —OCF 2 H, —SR 8 , —N(R 8 )S(═O) 2 R 9 , —S(═O) 2 N(R 8 ) 2 , —S(═O)R 9 , —S(═O) 2 R 9 , —C(═O)R 9 , —CO 2 R 8 , —N(R 8 ) 2 , —C(═O)N(R 8 ) 2 , —N(R 8 )C(═O)R 9 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 alkoxy. 
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein each R 1  is independently halogen, —CN, —OH, —OCF 3 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 alkoxy. 
     
     
         22 . The pharmaceutical composition of  claim 20 , wherein each R 1  is independently halogen, —OCF 3 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy. 
     
     
         23 . The pharmaceutical composition of  claim 20 , wherein each R 1  is independently is halogen. 
     
     
         24 . The pharmaceutical composition of any one of  claims 1 - 23 , wherein n is 1. 
     
     
         25 . The pharmaceutical composition of any one of  claims 1 - 19 , wherein n is 0. 
     
     
         26 . The pharmaceutical composition of any one of  claims 1 - 15 , wherein n is 0 and R 4  is H, —CN, —NO 2 , —OH, —OCF 3 , —OCH 2 F, —OCF 2 H, —SR 8 , —N(R 8 )S(═O) 2 R 9 , —S(═O) 2 N(R 8 ) 2 , —S(═O)R 9 , —S(═O) 2 R 9 , —C(═O)R 9 , —CO 2 R 8 , —N(R 8 ) 2 , —C(═O)N(R 8 ) 2 , —N(R 8 )C(═O)R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted C 2 -C 7 heteroaryl. 
     
     
         27 . The pharmaceutical composition of  claim 26 , wherein R 4  is H, —CN, —OH, —OCF 3 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 alkoxy. 
     
     
         28 . The pharmaceutical composition of  claim 1 , wherein the compound of Formula (I) has the structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 
     
     
         29 . A pharmaceutical composition comprising 1) a first therapeutic agent, 2) a second therapeutic agent, and 3) at least one pharmaceutically acceptable excipient, wherein the first therapeutic agent has the structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 
     
     
         30 . The pharmaceutical composition of any one of  claims 1 - 29 , wherein the second therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, an ataxia telangiectasia mutated (ATM) kinase inhibitor, an ataxia telengiectasia and Rad3 related (ATR) kinase inhibitor, a poly ADP-ribose polymerase (PARP) inhibitor, a cyclin-dependent kinase (CDK) 4/6 inhibitor, a checkpoint kinase 1 (Chk1) inhibitor, a signal transducer and activator of transcription 3 (STAT3) inhibitor, a mechanistic target of rapamycin (mTOR) inhibitor, or a Janus Kinase 2 (JAK2) inhibitor. 
     
     
         31 . The pharmaceutical composition of any one of  claims 1 - 30 , wherein the second therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor. 
     
     
         32 . The pharmaceutical composition of any one of  claims 1 - 30 , wherein the second therapeutic agent is an ataxia telangiectasia mutated (ATM) kinase inhibitor. 
     
     
         33 . The pharmaceutical composition of any one of  claims 1 - 30 , wherein the second therapeutic agent is an ataxia telengiectasia and Rad3 related (ATR) kinase inhibitor. 
     
     
         34 . The pharmaceutical composition of any one of  claims 1 - 30 , wherein the second therapeutic agent is a poly ADP-ribose polymerase (PARP) inhibitor. 
     
     
         35 . The pharmaceutical composition of any one of  claims 1 - 30 , wherein the second therapeutic agent is a cyclin-dependent kinase (CDK) 4/6 inhibitor. 
     
     
         36 . The pharmaceutical composition of any one of  claims 1 - 30 , wherein the second therapeutic agent is a checkpoint kinase 1 (Chk1) inhibitor. 
     
     
         37 . The pharmaceutical composition of any one of  claims 1 - 30 , wherein the second therapeutic agent is a signal transducer and activator of transcription 3 (STAT3) inhibitor. 
     
     
         38 . The pharmaceutical composition of any one of  claims 1 - 30 , wherein the second therapeutic agent is a mechanistic target of rapamycin (mTOR) inhibitor. 
     
     
         39 . The pharmaceutical composition of any one of  claims 1 - 30 , wherein the second therapeutic agent is a Janus Kinase 2 (JAK2) inhibitor. 
     
     
         40 . A method for treating cancer or Down's Syndrome in a subject comprising administering to the subject in need thereof a pharmaceutical composition of any one of  claims 1 - 39 . 
     
     
         41 . The method of  claim 40 , wherein the disease is cancer. 
     
     
         42 . The method of  claim 41 , wherein the cancer is brain cancer, glioblastoma multiforme, medulloblastoma, astrocytomas, brain stem gliomas, meningiomas, oligodendrogliomas, melanoma, lung cancer, breast cancer, or leukemia. 
     
     
         43 . The method of  claim 40 , wherein the disease is Down's Syndrome.

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